Project Summary Hexavalent chromium [Cr(VI)] is firmly established as a human carcinogen by epidemiological studies in occupationally exposed groups from different countries. The presence of this toxic metal at numerous Superfund sites and in drinking water across many states has also raised significant public health concerns regarding cancer and other health risks associated with environmental exposures to Cr(VI). Ingestion of Cr(VI) through drinking water produced clear evidence of carcinogenicity in the small intestine of mice. The low-dose extrapolation of these animal data to environmental risks in humans requires knowledge of the mechanism of the carcinogenic action for Cr(VI), which dictates the use of specific extrapolation models. Cr(VI) generates Cr-DNA adducts as the most abundant form of DNA damage but these adducts are weakly duplex-distorting and do not induce classic DNA damage responses. This project will investigate a hypothesis on a major role of DNA repair products of the initially formed Cr-DNA damage in the activation of noncanonical branches of genotoxic stress signaling. We will also examine the biochemical processes governing the responsiveness of the stress-sensitive transcription factor p53 and a protective G1 checkpoint to Cr-DNA damage. The completion of this work is expected to provide mechanistic explanations for unusual genetic features of Cr(VI)-induced lung tumors and improve human risk assessment.